Original Contributions |

Clinical Characterization of a Kindred With a Novel 12-Octapeptide Repeat Insertion in the Prion Protein Gene

Neeraj Kumar, MD; Bradley F. Boeve, MD; Brendon P. Boot, MBBS; Carolyn F. Orr, MBChB, PhD; Joseph Duffy, PhD; Bryan K. Woodruff, MD; Anil K. Nair, MD; Jay Ellison, MD, PhD; Karen Kuntz, RN; Kejal Kantarci, MD; Clifford R. Jack, MD; Barbara F. Westmoreland, MD; Julie A. Fields, PhD; Matthew Baker, BS; Rosa Rademakers, PhD; Joseph E. Parisi, MD; Dennis W. Dickson, MD
Arch Neurol. 2011;68(9):1165-1170. doi:10.1001/archneurol.2011.187.
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Objective To report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene, PRNP.

Design Clinical description of a kindred.

Setting Mayo Clinic Alzheimer Disease Research Center (Rochester, Minnesota).

Subjects Two pathologically confirmed cases and their relatives.

Main Outcome Measures Clinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses, and neuropathologic features.

Results The proband was a woman with clinical and neuroimaging features of atypical frontotemporal dementia and ataxia. Generalized tonic-clonic seizures developed later in the disease course, and electroencephalography revealed spike and wave discharges but no periodic sharp-wave complexes. Her affected sister and father also exhibited frontotemporal dementia–like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in the disease course. Genetic analyses in the proband identified a novel defect in PRNP, with 1 mutated allele carrying a 288–base pair insertion consisting of 12 octapeptide repeats. Neuropathologic examination of the proband and her sister revealed prion protein–positive plaques and widespread tau-positive tangles.

Conclusions This kindred has a unique combination of clinical and neuropathologic features associated with the largest base pair insertion identified to date in PRNP and underscores the need to consider familial prion disease in the differential diagnosis of a familial frontotemporal dementia–like syndrome.

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Figure 1. Pedigree of the proband's family. The square symbol indicates a male family member; circles, female members; shaded symbols, family members with dementia; diagonal lines over symbols, individuals who died; c, the individual's current age; d, age at death; and o, age at the onset of symptoms. The arrow indicates the proband.

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Figure 2. Magnetic resonance images of case II-3 (proband). A, Coronal T1-weighted (top row) and axial fluid attenuation inversion recovery (bottom row) images. Note the severe symmetric bifrontal atrophy with mild atrophy of the amygdalae and hippocampi. Although there is increased signal in the periventricular white matter anteriorly, no signal changes are present in the basal ganglia (not shown) or cerebral cortex. B, Midline T1-weighted sagittal images showing marked thinning of the corpus callosum, atrophy along the mesial frontoparietal cerebrum as well as the midline cerebellum, and a mildly generous fourth ventricle.

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Figure 3. Electroencephalogram of case II-3 (proband) at age 51 years. A, Diffuse slowing with generalized spike and sharp-wave discharges. B, Marked activation of the generalized spike and wave discharges with photic stimulation.

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Figure 4.PRNP gene octarepeat insertions. A, PRNP octarepeat nomenclature with the nucleotide composition of all octarepeats observed in the proband's mutated allele. B, The PRNP gene with the relative position and order of the 5 octarepeats seen in the wild-type allele. C, Position and composition of the mutation. The 12-octarepeat mutation equates to a 288–base pair insertion and is underlined. Most of the PRNP insertions occur between the second R2 and R3.




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